Most of the current treatments of neuroblastoma and other cancers target the tumor cell itself.  For example, chemotherapy agents like cyclophosphamide and cisplatin kill rapidly dividing cells (i.e. tumor cells), radiation is beamed directly at tumors, and the surgeon removes visible masses.  Although targeting the cancer cells with these methods has been beneficial, the success rate for curing neuroblastoma is nowhere near where we would like to be.  We must continue to look in new directions for effective treatments.

Metastatic tumors are tumor cells that spread from the original tumor to distant sites of the body, their presence signifies an aggressive tumor. The sites of metastatic spread are not random.  Neuroblastoma most commonly spreads to the bone marrow (70%) and bone (56%), and less commonly to the lymph nodes, liver, or soft covering of the brain [1].   Bone metastases, the focus of this article, cause problems for children because they are painful, they weaken the bone leading to fractures, and they are a common place for recurrent tumors.

In the late 1800’s, a forward thinking surgeon named Stephen Paget introduced his hypothesis of why tumors spread in set patterns. He recognized that tumor cells (seeds) need the body to survive and that they will grow best in those sites where the normal environment (soil) is the most fertile for them[2].  This theory is known as the seed and soil hypothesis and provides the rationale behind a new direction for fighting tumors:  changing the soil so the seeds don’t grow.  In this article I hope to explain the environment of the bone, how neuroblastoma tumor cells grow there, and a new trial to interrupt their interactions.

Normal Bone

Bones provide form and structure to our limbs and protection to our heart, lungs and brain.  The bone, or cortical bone, is the hard outer layer surrounding the bone marrow, the site of production of blood cells.  It is important to understand that bone and bone marrow are separate organs; although they are located close together, the cells that reside in each and the functions each serves in day-to-day activities are different.  Although bone appears solid and seemingly immovable, it is actually quite dynamic.  It grows as the child grows, strengthens areas that are weak, and heals after breaks. 

Three key players maintain cortical bone:  the bony matrix, osteoclasts and osteoblasts.  The bony matrix is a hard concrete-like structure that is mostly made of calcium.  To make it stronger collagen is woven throughout, similar to rebar-reinforced block of concrete.  Embedded within this structure are numerous chemicals that act as growth factors, encouraging the cells whose job it is to maintain the matrix.  (Figure 1)

Osteoclasts dissolve and destroy old matrix so that it can be replaced.  These cells use acids and enzymes to break down the calcium and collagen structure and then absorb some of the waste products into themselves.  As they work, they form physical cavities within the bone matrix.  These cavities need to be filled with new matrix, a function performed by osteoblasts.  Osteoblasts are also important for bone growth so are very busy in growing children.  Osteoclasts and osteoblasts talk back and forth through chemical signals.  It is important that they balance one another.  If osteoblasts become too active, the bone may become too thick or misshaped. Overactive osteoclasts can weaken the bone leading to breaks.

Neuroblastoma Metastases to Bone

Almost all children with neuroblastoma have a primary tumor mass.  This is where the neuroblastoma began and grew to form an actual tumor.  These primary masses are usually found in the adrenal gland or along the nervous system.  For about half of these children, tumor cells will be detected elsewhere as well.  These other sites of disease are called metastases and are the oncologist’s initial predictor of how aggressive the tumor will be.  The mechanisms behind the cause of metastases are beyond the scope of this article, but some general points can aid understanding bone metastatses.  In order for a metastasis to occur, tumor cells must break free of the primary mass and circulate around the body, frequently via the blood stream or lymphatic system.  While circulating, they are looking for other areas that would provide them with a good growth environment.